Title: Aryl-substituted and benzo-annulated cyc/osal-derivatives of 2',3'-dideoxy-2',3'-didehydrothymidine monophosphate--correlation of structure, hydrolysis properties and anti-HIV activity
Authors: Ducho, Christian ×
Balzarini, Jan
Naesens, Lieve
De Clercq, Erik
Meier, Chris #
Issue Date: Mar-2002
Series Title: Antiviral chemistry & chemotherapy vol:13 issue:2 pages:129-41
Abstract: The synthesis of phenyl-substituted and benzoannulated cycloSal phosphate triesters of the nucleoside analogue 2',3'-dideoxy-2',3'-didehydrothymidine (d4T, Zerit) as lipophilic, membrane-soluble pronucleotides is described. The cycloSal moiety was introduced by using cyclic chlorophosphite agents prepared from phenyl-substituted saligenin derivatives and ortho-hydroxymethylated naphthols, respectively. Hydrolysis studies (HPLC analysis) of the triesters 2, 3 showed a range of hydrolytic stability from 1.4 h up to 5.1 h and the stability could be correlated with the substitution pattern in the cycloSal moiety. A slight decrease of their stability was observed, if phenyl-substituted derivatives were hydrolyzed in human CEM/O cell extracts. D4T and thymine, possible products of enzymatic cleavage of the pronucleotides, were not detected in the cell extracts. A further investigation of the hydrolysis process was performed by 31P-NMR spectroscopy. This technique allowed a precise monitoring of the degradation products and the exact determination of the product ratio. Finally, the newly synthesized compounds were tested concerning their antiviral activity against HIV in vitro. A strong correlation of the hydrolysis properties and the antiviral activity was found. 3-phenyl-cycloSal-d4TMP showed a threefold increase in its anti-HIV-1 activity and retained full activity in thymidine kinase (TK) deficient cells, indicative of a successful TK-bypass.
ISSN: 0956-3202
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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